A primary goal of this project is the synthesis of analogues of the huperzine alkaloids. Huperzine A and B belong to the family o lycopodium alkaloids and were recently isolated from the club moss lycopodium serratum Thumb. This plant has been used in Chinese traditional medicine for the treatment of myasthenia gravis (MG) and senile memory loss (Alzheimer's dementia): diseases characterized by low levels of acetylcholine. Huperzine A and huperzine B are potent reversible inhibitors of acetylcholinesterase, the enzyme responsible for acetylcholine degradation. Several studies reveal the positive effect of the huperzine alkaloids on learning and memory improvement. Clinical studies in China demonstrated the safety and efficacy of huperzine A in treatment of senile memory disorders. The successful implementation of this project will provide access to numerous structural analogues. Structure activity studies will be carried out to determine important pharmacophores, which will help in the design of new drugs with higher intrinsic activity and improved therapeutic index. Furthermore, data from the structure activity studies will be of value for characterization of the enzyme AChE. This project is part of a broader long range plan directed toward application of the tandem photocyclization intramolecular ylide-alkene addition reaction to the synthesis of biologically active and medicinally important compounds. This procedure provides a means for construction of up to three rings and six-chiral centers in a single experimental operation from relatively simple starting materials. The proposed studies will demonstrate the significant potential of this process for the stereocontrolled synthesis of natural products. The synthesis plan profits from the considerable flexibility of the photoarylation reaction and provides efficient access to several hyperzine analogs.